The past 5 years have seen a dramatic increase in the abuse of synthetic cathinones (e.g., MDPV and methylone), which are marketed as bath salts, and are widely available for purchase on the internet and in local shops as safe and legal highs. In addition to a high potential for abuse, bath salts also have a high potential fr toxicity, characterized by severe cardiovascular and neuropsychiatric complications. Although the mechanisms that contribute to these high rates of abuse and toxicity are currently unclear, it is important to note that bath salts are most often mixtures of multiple psychoactive drugs, including mixtures of two different synthetic cathinones, or mixtures of a synthetic cathinone and caffeine. This proposal consists of three independent aims focused on comparing the reinforcing effectiveness, relapse-related behaviors, and toxic effects of bath salts mixtures (MDPV + methylone, MDPV + caffeine, and methylone + caffeine) with those of synthetic cathinones alone (MDPV and methylone). This project combines well-established animal models of abuse (self-administration) and toxicity (cardiovascular recordings) with isobolographic analysis to evaluate the highly innovative hypotheses that common bath salts mixtures are (1) more potent and effective reinforcers than synthetic cathinones alone; (2) more effective at strengthening drug-stimuli associations involved in relapse than synthetic cathinones alone; and (3) more potent and effective at producing tachycardia and hypertension as well as other features of the bath salts toxidrome than synthetic cathinones alone. Together, the results of the proposed studies will provide essential information about factors that contribute to the high rates of bath salts abuse and toxicity. This new knowledge will guide development of novel and targeted treatments for the ever-increasing and evolving problem of bath salts abuse.